Long-term effects of ricin-mAb 35 on extraocular muscles of rabbits: potential treatment for strabismus.
نویسندگان
چکیده
PURPOSE The immunotoxin, ricin-mAb 35, composed of ricin conjugated to a monoclonal antibody against the nicotinic acetylcholine receptor of skeletal muscle, has been proposed as a potential new agent for treatment of focal muscle dystonias. It has been demonstrated that direct injection of ricin-mAb 35 into rabbit extraocular muscle (EOM) results in significant muscle loss within 1 week. In this study, the long-term myopathic effects of ricin-mAb 35 on extraocular muscle were investigated. METHODS Rabbit superior rectus muscles were injected with ricin-mAb 35 at a dose of 0.2 microg/kg, with the contralateral superior rectus muscle serving as the control. After 56 days, 105 days, and 1 year, the superior rectus muscles were removed and prepared for light or electron microscopy. Postinjection changes in muscle fiber morphometry and ultrastructure were examined. Immunohistochemical markers were used to identify inflammatory cellular infiltrate and myosin heavy chain (MHC) isoform expression. RESULTS Despite evidence of ongoing regeneration, treated muscles continued to show a decrease in both myofiber number and in total cross-sectional area 56 and 105 days after injection. Individual myofiber cross-sectional areas were markedly heterogeneous at 56 days. Myofiber number and muscle cross-sectional area returned to normal 1 year after injection, but pronounced heterogeneity of myofiber size remained. The most significant changes in myosin heavy chain (MHC) isoform expression occurred in the orbital layer, where, at 56 and 105 days, there were increased numbers of fast and neonatal myofibers and decreased numbers of slow myofibers. In the global layer, after both 105 days and 1 year, there was a decrease in myofibers that were positive for slow, neonatal, and developmental MHC expression. CONCLUSIONS EOM injection with ricin-mAb 35 results in a sustained decrease in muscle mass at 105 days after injection, with subtler morphometric changes persisting even to 1 year. Changes in muscle force development as a result of ricin-mAb 35 injection are currently under investigation. This novel immunotoxin may be useful in the treatment of strabismus if these studies show sustained weakness in treated muscles.
منابع مشابه
Acute effects of the skeletal muscle-specific immunotoxin ricin-mAb 35 on extraocular muscles of rabbits.
PURPOSE To determine the acute histologic and ultrastructural effects of a recently developed muscle-specific immunotoxin, ricin-mAb 35. METHODS Graduated doses of ricin-mAb 35, composed of ricin conjugated to a monoclonal antibody against the nicotinic acetylcholine receptor of skeletal muscle, were injected into one superior rectus muscle in rabbits. After 3, 7, and 14 days, both superior r...
متن کاملExtraocular muscle force generation after ricin-mAb35 injection: implications for strabismus treatment.
PURPOSE Ricin-mAb35 is an immunotoxin targeted against skeletal muscle. Previously, we have shown that injection of ricin-mAb35 into rabbit extraocular muscle results in long-term muscle loss, and we have proposed this as a potential treatment for strabismus. In this study, we assessed the effects of ricin-mAb35 injection on extraocular muscle force generation. METHODS Ricin-mAb35, 0.2 microg...
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PURPOSE To examine force generation and duration of effect of botulinum toxin pretreatment, followed by injection of ricin-mAb35 in extraocular muscle. METHODS In normal adult rabbits, one superior rectus muscle was injected with either 5 units botulinum toxin or 1/50 maximally tolerated dose for rats (rMTD) of ricin-mAb35. Additional rabbits were first injected with 5 units botulinum toxin, ...
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PURPOSE Botulinum toxin type A and, more recently, the immunotoxin ricin-mAb35 have been effective as means of pharmacologically weakening the extraocular muscle. However, currently there are no drug treatments to strengthen an underacting extraocular muscle. In limb muscle, treatment with insulin-like growth factor causes myofiber hypertrophy. In this study, the short-term effects of insulin-l...
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PURPOSE Currently, no drug treatment is available for strengthening underacting extraocular muscles (EOM) in strabismus. We showed previously that single injections of insulin-like growth factor (IGF-1) result in significant but short-term increases in muscle force generation. This study examined the effects of sustained release of IGF-1 on force generation in rabbit superior rectus muscles. ...
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عنوان ژورنال:
- Investigative ophthalmology & visual science
دوره 43 3 شماره
صفحات -
تاریخ انتشار 2002